Capecitabine

Uses

Colorectal Cancer: Capecitabine is used for a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. It is used for first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.

Breast Cancer: Capecitabine in combination with docetaxel is used for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy. Monotherapy is also used for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not used.

Pancreatic Cancer: Capecitabine is used for the first line treatment of patients with locally advanced and metastatic pancreatic cancer in combination with gemcitabine.

Oesophagogastric Cancer: Capecitabine is used for the first line treatment of patients with advanced oesophagogastric cancer.

Capecitabine is also used to associated treatment for these conditions: Duke's C Colon cancer, Esophageal Cancers, Hepatobiliary Cancers, Malignant Neoplasm of Stomach, Metastatic Breast Cancer, Metastatic Colorectal Carcinoma, Pancreatic Cancer Metastatic, Refractory Fallopian Tube Carcinoma, Metastatic pancreatic endocrine carcinoma, Refractory Ovarian cancer, Refractory peritoneal cancer, Refractory, metastatic Colorectal carcinoma

How Capecitabine works

Capecitabine is a prodrug that is selectively tumour-activated to its cytotoxic moiety, fluorouracil, by thymidine phosphorylase, an enzyme found in higher concentrations in many tumors compared to normal tissues or plasma. Fluorouracil is further metabolized to two active metabolites, 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), within normal and tumour cells. These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deaxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, therefore a deficiency of this compound can inhibit cell division. Secondly, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis through the production of fraudulent RNA.

Dosage

Capecitabine dosage

In case of stage-III colon cancer and locally advanced or metastatic breast cancer: 1.25 gm/m2 twice daily for 14 days, followed by a 7-day interval, given as 3-week cycles for a total 8 cycles .

For metastatic colorectal cancer, in combination therapy it is administered as 0.8-1 gm/m2 twice daily for 14 days repeated after 7 days interval.

Side Effects

myocardial infarction, angina; hand-foot syndrome (numbness, tingling, pain, redness, or blistering of the palms of the hands and soles of the feet). This can lead to the disappearance of fingerprints in some patients; diarrhea (sometimes severe), nausea, stomatitis; neutropenia, anemia, thrombocytopenia; Hyperbilirubinemia.

Precaution

Patients receiving therapy with capecitabine should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced. During therapy, tablets should not be broken to adjust the dose.

Interaction

May interact with warfarin and increase bleeding risk. May inhibit CYP2C9 enzyme, and therefore increase levels of substrates such as phenytoin and other substrates of CYP2C9 enzymes. The concomitant use of leucovorin is not recommended as it increases the toxicity of capecitabine without any apparent advantage in response rate.

Food Interaction

• Take with food. Take within 30 minutes of the end of breakfast and dinner.

Capecitabine multivitamins interaction

[Major] MONITOR CLOSELY: Coadministration with folate therapy may potentiate the pharmacologic effects of 5-fluorouracil (5-FU).

The exact mechanism of interaction is unknown.

Although enhancement of 5-FU cytotoxicity may be used to advantage in some cancer patients, increased toxicity should also be considered.

Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.

In a clinical study consisting of 148 patients with advanced untreated colorectal cancer, weekly administration of 5-FU (600 mg

However, the combination was also more toxic than 5-FU alone, as evidenced by a higher incidence of grade 3 to 4 diarrhea (19.5% versus 8.5%) and conjunctivitis (26.5% versus 5.6%), as well as one recorded toxic death versus none.

No differences in median survival and time to progression were observed between the two groups.

Similar results were observed in another study with capecitabine, a prodrug of 5-FU.

The interaction has also been reported with folic acid.

A published case report describes two patients who were hospitalized for presumed 5-FU toxicity (anorexia, severe mouth ulceration, bloody diarrhea, vaginal bleeding) during concomitant treatment with a multivitamin containing folic acid (0.5 mg in one and 5 mg in the other).

Both patients tolerated subsequent courses of 5-FU at the previous dosage following discontinuation of the multivitamin.

Another published report describes a breast cancer patient who died during treatment with capecitabine (2500 mg

The patient developed diarrhea, vomiting, and hand-foot syndrome eight days after starting capecitabine therapy.

Her condition improved briefly following discontinuation of capecitabine and then folic acid, but she subsequently developed necrotic colitis and died from septic shock and vascular collapse.

Caution is advised if 5-FU or any of its prodrugs (e.g., capecitabine, tegafur) are prescribed in combination with leucovorin.

A lower dosage of 5-FU or the prodrug may be required.

Therapy with leucovorin and fluorouracil should not be initiated or continued in patients with symptoms of gastrointestinal toxicity until such symptoms have resolved.

Closely monitor patients with diarrhea until it resolves.

Monitor for other potential toxicities of 5-FU such as neutropenia, thrombocytopenia, stomatitis, cutaneous reactions, and neuropathy.

Patients should be instructed to avoid taking folic acid supplementation or multivitamin preparations containing folic acid without first speaking with their physician.

Capecitabine Drug Interaction

Moderate: denosumab, denosumabUnknown: naproxen, naproxen, apixaban, apixaban, metoprolol, metoprolol, metoprolol, metoprolol, polyethylene glycol 3350, polyethylene glycol 3350, bioflavonoids, bioflavonoids, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Capecitabine Disease Interaction

Major: infections, coronary artery disease, myelosuppression, renal dysfunctionModerate: dehydration, hepatic dysfunction

Elimination Route

Readily absorbed through the GI tract (~70%)

Half Life

45-60 minutes for capecitabine and its metabolites.

Elimination Route

Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose.About 3% of the administered dose is excreted in urine as unchanged drug.

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Capecitabine is contraindicated in patients with known dihydropy rimidine dehydrogenase (DPD) deficiency, it is also contraindicated in patients with severe renal impairment (creatinine clearance below 30 ml/min), and in patients with known hypersensitivity to Capecitabine.

Acute Overdose

Symptoms: Nausea, vomiting, diarrhoea, GI irritation and bleeding, bone marrow depression.

Management: Supportive treatment aimed at correcting the presenting clinical manifestations.

Storage Condition

Product should be stored at a dry place of controlled room temperature below 30° C and kept out of the reach of children.

Innovators Monograph

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